The Genetics of TDP-43 Type C Neurodegeneration: A Whole-Genome Sequencing Study and Literature Review

Frontotemporal lobar degeneration TDP43 type C (TDP-C) is a rare and unique neurodegenerative disease that attacks the anterior temporal lobe. Recently, it was shown that Annexin-A11 and TDP-43 coaggregate specifically in TDP-C. Current literature on the genetic associations with TDP-C, reviewed here, lacks a discernible corpus of robust or replicated findings. In this study, using blood tissue, we completed whole genome sequencing to investigate ANXA11 and TARDBP genetic variants for their association with TDP-C. Then, we completed genome-wide hypothesis-free analyses using artificial intelligence to identify rare pathogenic variants associated with TDP-C.

(1) We tested common variants in ANXA11 and TARDBP for their association with 37 TDP-C cases vs 290 controls. We attempted to replicate our findings in a different cohort of 467 TDP-C cases vs 3,153 controls and contrasted them with cohorts of TDP-A and TDP-B. (2) AI-guided analyses were completed to prioritize pathogenic rare variants associated with TDP-C in our cohort.

(1) Four common variants in ANXA11 (rs113772135, rs2789686, rs1079242, rs61860017) were significantly associated with TDP-C in the discovery cohort and replicated in the other cohort of TDP-C but not in TDP-A or TDP-B, providing evidence for ANXA11 specific association with TDP-C. Rs1079242-A showed the most robust replication (p = 7.35 × 10^-05) and correlates with higher ANXA11 level in CSF (p = 4 × 10^-11). No associations were found between TARDBP and TDP-C (p > 0.05). Using AI-guided rare variant analyses, we identified a pathogenic variant in FIG4, a gene that has been implicated in amyotrophic lateral sclerosis (ALS). Because of the observed potential genetic overlap between some ALS genes and TDP-C, we leveraged mendelian randomization and found that ALS genetic load is associated with TDP-C risk (p = 0.0046).

This study provides replicated evidence for the association between common variants in ANXA11 with TDP-C. Knowing rs1079242-A affects ANXA11 level in CSF, future studies may aim to investigate ANXA11 level as potential CSF biomarker for TDP-C. Moreover, FIG4 and ANXA11 have been implicated in the inositol pathway. Our results provide novel insights into the genetic risk of TDP-C and offer new clues about its underpinning mechanisms.